Due to its antimicrobial activity, chlorhexidine gluconate, a salt of chlorhexidine with gluconic acid, is widely used in forms of aqueous solutions as local disinfectants for disinfection of fingers and skin, and disinfection of the site of surgery, disinfection of surgical tools, as well as for disinfection of operation rooms and sickrooms, washing and disinfection of conjunctival sac, disinfection of the skin on and around external genitalia. In addition, chlorhexidine gluconate is also widely used as a preservative to prevent growth of microorganisms in aqueous pharmaceutical preparations for external use and preparations for topical use such as, eye drops and nasal drops.
However, chlorhexidine gluconate by nature is prone to develop precipitates by forming scarcely soluble salts where other anions than gluconate are present. For instance, it is known that chlorhexidine gluconate aqueous solutions will develop precipitates over time in the presence of citrate or chloride ion. Therefore, either of citrate or chloride ion is an incompatible chemical species with chlorhexidine.
On the other hand, in most of the cases, aqueous pharmaceutical preparations such as eye drops and nasal drops contain chloride ion. A number of active drugs and excipients provide a source of chloride ion, such as, sodium chloride as an isotonic agent; inorganic chlorides such as potassium chloride, calcium chloride, and magnesium chloride; compounds used as pharmacologically active constituents such as pilocarpine hydrochloride (miotic), pyridoxine hydrochloride (vitamin B.sub.6), naphazoline hydrochloride (vasoconstricter), diphenhydramine hydrochloride (antihistamine), dibucaine hydrochloride (local anesthetic); and hydrochloric acid used as a pH adjusting agent during production of aqueous pharmaceutical preparations. Thus, inclusion of chloride ion is unavoidable in many of aqueous pharmaceutical preparations.
Therefore, in many of aqueous pharmaceutical preparations such as eye drops and nasal drops, it has been unallowable to simply employ chlorhexidine gluconate as a preservative.
In order to prevent precipitation of chlorhexidine in a chloride ion-containing aqueous solution, it is known to include a nonionic surface active agent in the solution. However, as nonionic surface active agents are prone to cause irritation to mucous membrane, it is unfavorable to include a nonionic surface active agent in preparations to be applied to mucous membranes such as, in particular, eye drops or nasal drops.
Thus, there exists a need for a method of maintaining, without inclusion of nonionic surface active agent, chlorhexidine gluconate stably in an aqueous pharmaceutical preparation in concurrent presence of chloride ion, as well as for an aqueous pharmaceutical preparation produced by such a method.